Diabetic kidney disease (DKD) is the most common cause of end stage renal disease (ESRD) in both type 1 and type 2 diabetes. Impaired autophagy is implicated in the development of DKD. In this application, we propose that increased (Pro)renin receptor (PRR) in diabetes, reduces autophagy in renal glomerular and tubular cells leading to development of DKD. Our preliminary in vitro and in vivo studies demonstrated that hyperglycemia increases PRR expression and activity, a process that is mediated by NFkB. Our data also suggested that PRR contributes to the development of renal inflammation, fibrosis, and albuminuria. In renal podocytes, mesangial, and inner medullary collecting duct cells, high-glucose-induced inhibition of SIRT1, stimulation of mTOR and PKC-ROS, impaired autophagy and enhanced apoptosis. Reduction in renal PRR expression reversed high glucose-induced intracellular signal abnormalities and improved autophagy. Based on these data, it is likely that diabetes-induced increase in renal PRR expression impairs autophagy, leading to cellular injury and directly contributes to development of DKD. The long-term goal of our research program is to elucidate novel glomerular and tubular mechanisms that involve PRR and contribute to the development of diabetes induced renal disease. To achieve this goal, we will utilize a rationale and novel integrated approaches, consisting of in vivo studies utilizing a novel inducible nephron specific PRR knockdown mouse model to manipulate tubular PRR and renal cortical interstitial administration of PRR shRNA to manipulate glomerular and cortical tubules PRR. These studies will be complemented by state-of-the-art in vitro cellular and molecular techniques including utilization of Laser scanning confocal microscopy. Based on our preliminary data, the central hypothesis of this proposal is that increased renal PRR expression and activity in diabetes contributes to development of renal tubular and glomerular inflammation, fibrosis, and cellular apoptosis by inhibiting autophagy via stimulation of SIRT1-FoxO3, PI3K-Akt-mTOR and PKC- ROS signaling pathways (Figure 1). In this proposal, we will pursue the following specific aims: Aim 1: To test the hypothesis that renal tubular PRR contributes to development of DKD by inhibiting SIRT1- FoxO3a-autophagy pathway, leading to tubular fibrosis and apoptosis. Aim 2: To test the hypothesis that PRR contributes to glomerular injury in diabetes by enhancing PI3K-AKT-mTOR signaling pathway in renal mesangial cells (RMCs) and podocytes, leading to reduction in autophagy activity, inflammation, increased matrix formation, and apoptosis. Aim 3: To test the hypothesis that PRR contributes to the development of DKD by stimulating PKC-NOX4-NFkB signaling pathway activity and inhibiting autophagy leading to enhanced renal inflammation, fibrosis and apoptosis. These studies are expected to identify novel mechanisms that contribute to development of DKD. These mechanisms could lead to development of new therapeutic strategies for treating DKD.